DESCRIPTION: Nitric oxide (NO) has been found to possess broad spectrum antimicrobial properties. Numerous mammalian cells have been found to possess inducible nitric oxide synthase (iNOS) activity after challenge with immunologic or inflammatory stimuli. However, it is unclear if NO radical (NO) itself or other forms of NO such as nitrosothiols or peroxynitrite (ONOO-) are the major effector molecules responsible for biological activity. Some of these intermediates have been found in body fluids during states of inflammation, suggesting a role for these compounds in host defense. Despite advances in understanding the complex biochemistry of NO, little is known about the redox forms responsible for the pleiotropic properties ascribed to NO. Moreover, despite the identification of several potential targets of NO, the precise molecular mechanisms of NO cytotoxicity are unknown. Using a convenient Salmonella typhimurium model to study the antimicrobial effects of nitric oxide, it is proposed to: Identify Salmonella genes which determine susceptibility to different redox forms of nitric oxide in vitro; Correlate Salmonella susceptibility to in vitro nitric oxide donors with susceptibility to cell-derived nitric oxide; and determine the in vivo virulence of mutants with altered nitric oxide susceptibility in innately resistant and susceptible mice.